Hydantoin derivsatives with affinity for somatostatin receptors

ABSTRACT

The invention provides compounds of formula (I) wherein X, Y, R 1 , R 2 , R 3  and R 4  are as defined in the description, and the preparation thereof. The compounds of the formula bind to somatostatin receptors and are useful as pharmaceuticals.

[0001] The present invention relates to novel hydantoin derivatives,their preparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

[0002] The invention provides compounds of formula I

[0003] wherein

[0004] X and Y independently are O or H, H,

[0005] R₁ is a group of formula

[0006] wherein the R_(a) independently are hydrogen, C₁₋₄ alkyl or aCH₃COO—CH(CH₃)—OCO—group and Z is a saturated or unsaturated aliphaticC₂₋₆ hydrocarbonic chain which is (a) optionally interrupted by —O— or—S— and (b) optionally substituted by C₁₋₄ alkyl or C₁₋₄ alkoxy groups,

[0007] R₂ is a group of formula —SO₂—Ar or —CH₂—Ar wherein Ar is phenylor naphthyl optionally mono- or di-substituted by hydroxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, trifluoromethyl, aminomethyl,dimethylaminocarbonyl, benzimidazolyloxy or morpholinocarbonyl, or by agroup of formula

[0008] wherein Q is CH₂, O, S or CO, the R_(b) independently arehydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, amino, halogen, hydroxy, aNH₂-(CH₂)₄-CH(NH₂)—COO—group or form together a methylenedioxy, and theR_(c) independently are hydrogen or C₁₋₄alkyl,

[0009] R₃ is hydrogen or C₁₋₄ alkyl and

[0010] R₄ is a group of formula

[0011] wherein R_(d) is hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄alkoxy, andR_(e) is hydrogen, C₁₋₄alkyl or benzyl,

[0012] in free base or acid addition salt form.

[0013] X and Y are preferably O.

[0014] R₁ preferably is —Z—NH₂, wherein Z is preferably an alkylenechain.

[0015] R₂ preferably is —SO₂—A_(r), wherein A_(r) is preferably anoptionally substituted phenyl.

[0016] R₃ preferably is H.

[0017] R₄ is preferably an optionally substituted 3-indolyl.

[0018] Any alkyl or alkoxy group as defined above preferably has one ortwo carbon atoms and more preferably is methyl or methoxy.

[0019] Halogen denotes fluorine, bromine or chlorine.

[0020] Depending on the nature of the substituents defined above, one ormore asymmetric carbons may be present in the molecule. All opticalisomers and their mixtures including the racemic mixtures are part ofthe present invention.

[0021] The compounds of formula I may be prepared over a process whichincludes the steps of reacting a compound of formula II

[0022] wherein X, Y, R₃ and R₄ are as defined above and R′₁ is R₁ asdefined above or a protected form of R₁, with a compound of formula III

R′₂—Hal  III

[0023] wherein R′₂ is R₂ as defined above or a protected form of R₂ andHal is chlorine, bromine or iodine, deprotecting the resulting productand recovering the thus obtained compound of formula I in free base oracid addition salt form.

[0024] A protected amino group in R′₁ is for example anN-butyloxycarbonyl (Boc)- or an N₃-residue. When in formula III, R′₂ isa group of formula —SO₂—A_(r), Hal is preferably chlorine. Thecondensation of the compound of formula 11 with the compound of formulaIII and the subsequent deprotection can be effected according to knownmethods, for example as described in Example 1.

[0025] Working up the reaction mixtures obtained and purification of thecompounds of formula I may also be carried out in accordance with knownmethods.

[0026] Acid addition salts may be produced from the free bases in knownmanner, and vice versa.

[0027] The starting compounds of formula II are known or may be producedby known methods. For example compounds of formula II wherein X and Yare O may be produced in accordance with the following reaction scheme,for example as described in Example 1:

[0028] The starting compounds of formulae III and V are known or may beproduced by known processes.

[0029] The compounds of formula I and their physiologically acceptableacid addition salts, hereinafter referred to as compounds of theinvention, have interesting pharmacological properties when tested invitro using somatostatin receptor expressing cell cultures and inanimals, and may therefore be used as pharmaceuticals.

[0030] In particular the compounds of the invention bind to somatostatinreceptors. More particularly they are selective agonists at Somatostatinsst₂ receptors, as determined in radioligand binding and secondmessenger studies [see for example K. Kaupmann et al., FEBS LETTERS1993, 331: 53-59].

[0031] The compounds of the invention are therefore indicated for use inanxiety, depression, schizophrenia, neurodegenerative diseases such asdementia, epilepsy, endocrinological disorders associated with an excessof hormone release such as: growth hormone (GH) glucagon or insulinsecretion, gastro-intestinal disorders, for the treatment of tumors andfor vascular disorders and immunological diseases.

[0032] The usefulness of the compounds of the invention in theseindications is confirmed in a range of standard tests as indicatedbelow:

[0033] At doses of about 0.3 to 3 mg/kg p.o., the compounds of theinvention increase exploratory behavior of mice in the open half of thehalf enclosed platform, a model which is predictable for anxiolyticactivity (Psychopharmacology, 1986, 89:31-37).

[0034] In the same half enclosed platform model, the compounds of theinvention at the above indicated doses increase vigilance andexploratory components of behavior of the mice. The compounds aretherefore indicated for the treatment of depression, schizophrenia anddementia, in particular of senile dementia of the Alzheimer type (SDAT).In addition, there is circumstantial clinical evidence for various typesof dementias to be associated with reduced somatostatin levels [see forexample J. Epelbaum et al., Clinical Reviews in Neurobiology 8: 25-44(1994)].

[0035] At doses of about 0.3 to 3 mg/kg p.o., the compounds of theinvention inhibit epileptic seizure in electrically and chemicallyinduced episodes in rats [A. Vezzani et al., Neuropharmacol., 30:345-352 (1991)].

[0036] Furthermore the compounds of the invention inhibit GH release incultured pituitary cells in vitro and depress serum GH and insulinlevels in the rat The test is carried out using male rats. The testsubstance is administered at varying, logarithmically staggered dosesemploying at least 5 rats per dose. 1 hour after s.c. administration ofthe test substance blood is taken. The determination of the blood serumGH and insulin levels is measured by radio-immunoassay. The compounds ofthe invention are active in this test when administered at a dosage inthe range of from 0.1 to 1 mg/kg s.c.

[0037] The inhibitory effect of the compounds on GH release may also beexamined after oral application to male rats with oestradiol implants.This test is carried out as follows:

[0038] A loop (length 50 mm Ø 3 mm) of silastic with 50 mg of oestradiolis implanted under the dorsal skin of anaesthetized male OFA rats whichhave a weight of ca. 300 g. At various times (1 to 6 months later),these animals, in a fasted state, are used repeatedly for tests. Thetest substances are active in this test at doses from 0.1 to 5 mg/kg,when GH level in the blood serum is determined by radio-immunoassay 1and 2 hours after oral administration.

[0039] The compounds of the invention are accordingly indicated for usein the treatment of disorders with an aetiology comprising or associatedwith excess GH-secretion, e.g. in the treatment of acromegaly as well asin the treatment of diabetes mellitus, especially complications thereof,e.g. angiopathy and various disorders associated with angiogenesis,proliferative retinopathy, dawn phenomenon and nephropathy.

[0040] The compounds of the invention also inhibit gastric and exocrineand endocrine pancreatic secretion and the release of various peptidesof the gastrointestinal tract, as indicated in standard tests using e.g.rats with gastric or pancreatic fistulae.

[0041] The compounds are thus additionally indicated for use in thetreatment of gastro-intestinal disorders, for example in the treatmentof peptic ulcers, disturbances of GI motility, enterocutaneous andpancreaticocutaneous fistula, irritable bowel syndrome, dumpingsyndrome, watery diarrhea syndrome, acute pancreatitis andgastro-intestinal hormone secreting tumors (e.g. vipomas, glucagonomas,insulinomas, carcinoids and the like) as well as gastro-intestinalbleeding. [see for example: Th. O'Dorisio et al., Advances Endocrinol.Metab. 1990,1:175-230].

[0042] The compounds of the invention are also effective in thetreatment of various kinds of tumors, particularly of sst₂ receptorbearing tumors, as indicated in proliferation tests with variousdifferent cancer cell lines and in tumor growth experiments in nude micewith hormone dependent tumors [see for example: G. Weckbecker et al.,Cancer Research 1994, 54: 6334-6337]. Thus the compounds can be used inthe treatment of, for example, cancers of the breast, the prostate, thecolon, the pancreas, the brain and the lung (small cell lung cancer).

[0043] For the above-mentioned indications, the appropriate dosage willof course vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from 0.1 toabout 50, preferably from about 0.5 to about 20 mg/kg animal bodyweight. In larger mammals, for example humans, an indicated daily dosageis in the range from about 1 to about 100, preferably from about 5 toabout 50 mg of an agent of the invention conveniently administered, forexample, in divided doses up to four times a day or in sustained releaseform.

[0044] The compounds of the invention may be administered in free formor in pharmaceutically acceptable salt form or complexes. Such salts andcomplexes may be prepared in conventional manner and exhibit the sameorder of activity as the free compounds.

[0045] The present invention also provides a pharmaceutical compositioncomprising a compound of the invention in free base form or inpharmaceutically acceptable acid addition salt form in association witha pharmaceutically acceptable diluent or carrier. Such compositions maybe formulated in conventional manner. The compounds may be administeredby any conventional route, for example parenterally e.g. in form ofinjectable solutions or suspensions, enterally, preferably orally, e.g.in the form of tablets or capsules or in a nasal or a suppository form.

[0046] Moreover the present invention provides the use of the compoundsof the invention for the manufacture of a medicament for the treatmentof any condition mentioned above.

[0047] In still a further aspect the invention provides a method for thetreatment of any condition mentioned above, in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of a compound of the invention.

[0048] The following examples illustrate the invention. The temperaturesare given in degrees Celsius and are uncorrected.

EXAMPLE 1(+/−)-1-(2′,5′-dichloro-1′-benzenesulfonyl)-3-(5′-amino-n-pentanyl)-5-[(indol-3-yl)-methyl)]-imidazolidine-2,4-dione

[0049] Sodium hexamethyldisilazide (1.1 mmol, 1.1 mL 1 M solution inTHF) is added to a stirred solution of3-[5′-amino-(N-t-butyloxycarbonyl)-n-pentanyl]-5-[(indol-3-yl)methyl]-imidazolidine-2,4-dione(415 mg, 1.0 mmol) in 5 mL dry tetrahydrofuran (THF) at −40° underargon. After 30 minutes, 2,5-dichlorobenzenesulfonyl chloride (270 mg,1.1 mmol) is added and the solution is allowed to stir overnight at roomtemperature. Saturated ammonium chloride solution is added and themixture concentrated on a rotary evaporator. The mixture is thendissolved in ethyl acetate, extracted with brine, dried (sodium sulfate)and concentrated to a viscous oil. This crude product is purified bymedium pressure liquid chromatography (MPLC) over silica gel (59 gSiO₂0.015-0.04 mm; ethylacetate-hexane 2:1) to give a colorless viscousoil.

[0050] The so obtained product (530 mg, 0.85 mmol) is dissolved in 6 mLof dichloromethane and iodotrimethylsilane (204 mg, 2.0 mmol) is added.After stirring for 10 minutes at room temperature, potassium bicarbonate(4 mL, 2N solution) is added and the resulting solution stirred for 15minutes. The organic phase is separated, dried (sodium sulfate) andconcentrated to give the crude free base. This base is dissolved in 4 mLethanol and ethereal HCl solution (1 mL, ca. 1N solution) is added. Thesolution is cooled and ether added whereupon the hydrochloride saltcrystallizes out of solution. Filtration provides the product inhydrochloride salt form; mp. 157-159°.

[0051] The starting imidazolidine-dione is prepared as follows:

a)N-α-t-butyloxycarbonyl-d,1-tryptophan-[5-amino-(N-t-butyloxycarbonyl)-n-pentanyl]amide

[0052] To a stirred solution of mono-N-Boc-1,5-pentanediamine (1.27 g,6.3 mmol) and d,1-tryptophan (2.12 g, 7.0 mmol) in 30 mL THF is addeddicyclohexylcarbodiimide (DCC) (1.54 g, 7.5 mmol) at room temperature.After one hour the mixture is filtered to remove the precipitateddicydohexylurea and concentrated in vacuo. Ether is added, the mixtureis filtered and then cooled, whereupon the product crystallizes out ofsolution. Filtration yields the product as a light brown powder; mp.97-98°.

b)3-[5′-amino-(N-t-butyloxycarbonyl)-n-pentanyl]-5-[(indol-3-yl)methyl)]-imidazolidine2,4-dione

[0053] The product obtained under a) (2.93 g, 6.0 mmol) is dissolved in50 mL THF and heated under reflux with tetrabutylammonium fluoridetrihydrate (5.68 g, 18 mmol). After 24 hours the mixture is concentratedin vacuo. The residue is dissolved in ethylacetate, extracted withbrine, dried (sodium sulfate) and concentrated to a viscous brown oil.MPLC chromatography (138 g SiO₂; ethylacetate-hexane 2:1) gives theproduct as a light yellow oil which crystallizes upon standing. Ananalytical sample is prepared by recrystallization fromethylacetate-hexane; mp. 136-137°.

[0054] The compounds of formula I wherein R₁, R₂, R₃ and R₄ are asdefined in the following table 1 and X and Y are both O as well as thecompounds of formula I wherein R₁, R₂, R₃ and R₄ are as defined in thefollowing table 2, X is H, H and Y is O, are prepared in analogousmanner to Example 1. TABLE 1 Ex R₁ R₂ R₃ R₄ 2 —(CH₂)₅—NH₂ —SO₂-p-toluylH —CH₂-3 indolyl 3 ″ —SO₂-3,4-diMe—Ph ″ ″ 4 ″ —SO₂-m-CH₃—Ph ″ ″ 5 ″—SO₂-o-OMe—P ″ ″ 6 —CH₂CH═CH—(CH₂)₂—NH₂(cis) —SO₂-3,4-diOMe—Ph ″ ″ 7—(CH₂)₂—O—(CH₂)₂—NH₂ —SO₂-3,4-diOMe—Ph ″ ″ 8 —(CH₂)₄—NH₂—SO₂-3,4-diOMe—Ph ″ ″ 9 —(CH₂)₆—NH₂ —SO₂-3,4-diOMe—Ph ″ ″ 10 —(CH₂)₅—NH₂—SO₂-3-[(Me)₂NCO]-4- ″ ″ (5-benzimidazolyl-O)—Ph 11 ″—SO₂-p-(p-NH₂—Ph—O)—Ph ″ ″ 12 ″ —SO₂-3-CN-4-(p-OH—Ph—O)—Ph ″—CH₂-3-(7-CH₃- indolyl) 13 ″ —SO₂-3-NH₂CH₂-4-(p-OH—Ph— ″ —CH ₂-3-(7-CH₃-O)—ph indolyl) 14 ″ —SO₂-p-(p-OH—Ph—CO)—Ph ″ CH₂-3-indolyl 15 ″—SO₂-p-(p-OH—Ph—CH₂)—Ph ″ ″ 16 ″ —SO₂-p-(p-OH—Ph—O)—Ph ″ ″ 17 ″—SO₂-p-(—OH—Ph—S)—Ph ″ ″ 18 ″ —SO₂-p-(4-NH₂-2-pyridyl-O)—Ph ″ ″ 19 ″—SO₂-3-(morpholino-CO)-4-(p—Cl—Ph— H —CH₂-3-indolyl O)—Ph 204-piperidinyl-(CH₂)₂— —SO₂-3-[(Me)₂NCO]-4-(p-OH—Ph— ″ ″ O)—Ph 21—(CH₂)₅—NH₂ —SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ ″ Ph—O)—Ph 224-Me-1-piperazinyl-(CH₂)₂— —SO₂-3-[(Me)₂NCO]-4-(p-OMe—Ph— ″ ″ O)—Ph 23—(CH₂)₅—NH₂ —SO₂-3-[(Me)₂NCO]-4-[NH₂—(CH₂)₄— ″ ″ CH(NH₂)—COO—Ph—O]—Ph 24[MeCOO—CH(Me)—OCO—NH]— —SO₂-3-[(Me)₂NCO]-4-(p-OH—Ph— ″ ″ (CH₂)₅— O)—Ph25 —(CH₂)₅—NH₂ —SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ —(CH₂-3-(7-Cl-indolylPh—O)—Ph 26 —CH₂-(p-trans-NH₂- —SO₂-3-[(Me)₂NCO]-4-(p-OH—Ph— ″—CH₂-3-indolyl cyclohexyl) O)—Ph 27 —(CH₂)₅—N(Me)₂—SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ ″ Ph—O)—Ph 28 —(CH₂)₃-(1-imidazolyl)—SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ ″ Ph—O)—Ph 29 —(CH₂)₅—NH₂—SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ —CH₂-3-(7-Me- Ph—O)—Ph indolyl) 30—(CH₂)₅—NH₂ —SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— H —CH₂-3-(5-Me-indolylPh—O)—Ph 31 —(CH₂)₄—CH(Me)₂—NH₂ —SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″—CH₂-3-(7-Me-indolyl Ph—O)—Ph 32 —(CH₂)₃-(1-Me-4-imidazolyl)—SO₂-3[(Me)₂NCO]-4-(3-Cl-4-OH— ″ —CH₂-3-indolyl) Ph—O)—Ph 33 —(CH₂)₅—NH₂—SO₂-3-CH(CH₃)₂-4-(3-Cl-4-OH— ″ —CH₂-3-(7-Me-indolyl Ph—O)—Ph 34—(CH₂)₄—C(CH₃)₂—NH₂ —SO₂-3-[(Me)₂NCO]-4-(p—F—Ph—O)— ″ ″ Ph 35 ″—CH₂-3-[(Me)₂NCO]-4-(3-Cl-4- ″ ″ MeO—Ph—O)—Ph 36 ″—SO₂-3-[(Me)₂NCO]-4(3-Cl-4-OH— ″ ″ Ph—O)—Ph 37 ″—SO₂-3-[(Me)₂NCO]-4-(3-Cl-4-OH— ″ —CH₂-3- Ph—O)—Ph benzo[b]thienyl 38 ″—SO₂-3-[(Me)₂NCO]-4-(3-Cl-4- ″ —CH₂-1-(4-Me- MeO—Ph—O)—Phbenzimidazolyl) 39 —(CH₂)₄—C(CH₃)₂—NH₂ —SO₂-3-[(Me)₂NCO]-4-[(3,4- ″—CH₂-3-(7-Me-indolyl methylenedioxy-Ph—O)—Ph

[0055] TABLE 2 Ex R₁ R₂ R₃ R₄ 40 —CH₂—CH═CH—(CH₂)₂—NH₂ —CH₂—Ph H—CH₂-3-indolinyl 41 ″ ″ ″ —CH₂-3-indolyl 42 —(CH₂)₅—NH₂ ″ ″ ″ 43—CH₂-p-(aminomethyl)-Ph ″ ″ ″ 44 —(CH₂)₅—NH₂ —SO₂-3,4-dioMe—Ph ″ ″ 45 ″—SO₂-p-(p-OH—Ph— ″ ″ O)—Ph

[0056] The compounds of the above tables have been characterized asfollows: Example 3 FAB-MS: MH⁺=515 4 FAB-MS: MH⁺=523 8 FAB-MS: MH⁺=515 9FAB-MS: MH⁺=529 12 FAB-MS: MH⁺=602 NMR(DMSO): 0.4-1.1(6H, m), 2.3(2H,t), 2.4(3H, s), 2.9(1H, m), 3.05 (1H, m), 3.2-2.6(2H, s), 3.5(2H, d),5.2(1H, t), 6.8-7.1 (9H, m), 7.3(1H, m), 8.2(1H, m), 8.55(1Hm), 11.0(1H,s). 13 FAB-MS: MH⁺=606 NMR(DMSO): 0.4-1.6(6H, m), 2.4(3H, t), 2.5(2H,m), 2.9(1H, m), 3.1 (1H, m), 3.5(2H, m), 4.2(2H, m), 5.25(1H, m),6.7-7.1 (8H, m), 7.35(1H, m), 7.9(1H, m), 8.05(3H, s), 8.3(1H, m),8.75(3H, s), 9.75(1H, s), 11.1(1H, s). 14 Mp: 151-153° (HCl salt)FAB-MS: MH⁺=575 NMR(DMSO): 0.45-1.1(6H, m), 2.25(2H, m), 2.9(1H, m),3.05(1H, m), 3.2(2H, s), 3.65(1H, m), 3.7(1H, q), 3.85(3H, s), 5.2(1H,t), 6.9-8.2(13H, m), 11.0(1H, s). 15 FAB-MS: MH⁺=561 NMR(DMSO):0.4-1.0(6H, m), 2.25(2H, m), 2.85(1H, m), 3.05(1H, m). 3.2(2H, s),3.5(2H, d), 3.7(3H, s), 4.0(2H, s), 5.1(1H, t), 6.8-8.0(13H, m),11.0(1H, s). 16 FAB-MS: MH⁺=563 17 FAB-MS: MH⁺=579 19 FAB-MS: MH⁺=694 20FAB-MS: MH⁺=660 21 FAB-MS: MH⁺=668 NMR(Hcl salt; DMSO): 0.35-1.2(6H, m),2.45(2H, m), 2.85(3H, s), 3.0(3H, s), 2.85-3.15(2H, m), 3.5(2H, d),5.65(1H, t), 6.9-7.1(6H, r 7.2(1H, d), 7.35(1H, d), 7.5(1H, d), 7.75(3H,s), 8.0(2H, rr 10.4(1H, s), 11.1(1H, s). 22 ESI-MS: M⁺=689 23 Mp:189-191° (amorphous) 24 Mp: 107-111° (amorphous) 25 Mp: 198-203° 26 Mp:190-196° (amorphous) 27 ESI-MS: M⁺=696 28 ESI-MS: M⁺=691 29 FAB-MS:MH⁺=682 30 FAB-MS: MH⁺=682 31 FAB-MS: MH⁺=710 NMR(DMSO): 0.45-1.1(6H,m), 0.9(6H, 2s), 2.4(3H, s), 2.85(3H, s), 3.0(3H, s), 2.8-3.1(2H, m),3.5(2H, d), 5.65(1H, t), 6.8-7.05(6H, m), 7.2(1H, d), 7.3(1H, d),8.0(2H, m), 11.0(1H, s). 32 ESI-MS: M⁺=705 NMR(DMSO): 1.1(2H, m),1.8(2H, t), 2.8(3H, s), 2.95(3H, s), 3.05(2H, m), 3.5(2H, d), 3.55(3H,s), 5.6(1H, t), 6.45(1H, s), 6.85-7.05(5H, m), 7.2-7.5(4H, m), 8.0(2H,m), 10.3(1H, s), 10.95(1H, s) 33 ESI-MS: M⁺=653 34 ESI-MS: M⁺=678 35FAB-MS: MH⁺=674 NMR(DMSO): 0.9(6H, s), 0.8-1.4(6H, m), 2.4(3H, s),2.8(3H, s), 2.95(3H, s), 3.0-3.5(4H, m), 3.85(3H, s), 4.2(1H, t),4.35(1H, d), 4.8(1H, d), 6.8-7.35(10H, m), 10.9(1Hs). 36 FAB-MS: MH⁺=72837 FAB-MS: MH⁺=685 38 FAB-MS: MH⁺=697 39 ESI-MS: M⁺=704

What we claim is:
 1. A compounds of formula I

wherein X and Y independently are O or H, H, R₁ is a group of formula

wherein the R_(a) independently are hydrogen, C₁₋₄alkyl or aCH₃COO—CH(CH₃)OCO-group and Z is a saturated or unsaturated aliphaticC₂₋₆ hydrocarbonic chain which is (a) optionally interrupted by —O— or—S— and (b) optionally substituted by C₁₋₄ alkyl or C₁₋₄ alkoxy groups,R₂ is a group of formula —SO₂—Ar or —CH₂—Ar wherein Ar is phenyl ornaphthyl optionally mono- or di- substituted by hydroxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, trifluoromethyl, aminomethyl,dimethylaminocarbonyl, benzimidazolyloxy or morpholinocarbonyl, or by agroup of formula

wherein Q is CH₂, O, S or CO, the R_(b) independently are hydrogen,C₁₋₄alkyl, C₁₋₄alkoxy, amino, halogen, hydroxy, aNH₂-(CH₂)₄-CH(NH₂)—COO— group or form together a methylenedioxy, and theR, independently are hydrogen or C₁₋₄alkyl, R₃ is hydrogen or C₁₋₄ alkyland R₄ is a group of formula

wherein R_(d) is hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄alkoxy, and R_(e)is hydrogen, C₁₋₄alkyl or benzyl, in free base or acid addition saltform.
 2. A process for the preparation of a compound of formula I asdefined in claim 1, which includes the steps of reacting a compound offormula II

wherein X, Y, R₃ and R₄ are as defined in claim 1 and R′₁ is R₁ asdefined in claim 1 or a protected form of R₁, with a compound of formulaIII R′₂—Hal  III wherein R′₂ is R₂ as defined in claim 1 or a protectedform of R₂ and Hal is chlorine, bromine or iodine, deprotecting theresulting product and recovering the thus obtained compound of formula Iin free base or acid addition salt form.
 3. A pharmaceutical compositioncomprising a compound of formula I as defined in claim 1 in free baseform or in pharmaceutically acceptable acid addition salt form inassociation with a pharmaceutically acceptable carrier or diluent.
 4. Acompound of formula I as defined in claim 1 in free base form or inpharmaceutically acceptable acid addition salt form, for use as apharmaceutical.
 5. A compound of claim 1 in free base orpharmaceutically acceptable acid addition salt form, for use in thetreatment of conditions responsive to sst₂ receptor agonists.
 6. The useof a compound of claim 1 in free base or pharmaceutically acceptableacid addition salt form, as a pharmaceutical for the treatment ofconditions responsive to sst₂ receptor agonists.
 7. The use of acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, for the manufacture of a medicament for thetreatment of conditions responsive to sst₂ receptor agonists.
 8. Amethod for the treatment of conditions responsive to sst₂ receptoragonists to a subject in need of such treatment, which comprisesadministering to such subject a therapeutically effective amount of acompound of claim 1 in free base of pharmaceutically acceptable acidaddition salt form.